Tetrahydrofuran derivatives and their use as nk-1 antagonists

ABSTRACT

The present invention relates compounds of the formula (1): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  represent a variety of substituents; and pharmaceutically acceptable salts thereof. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.

[0001] This invention relates to a class of tetrahydrofuran compoundswhich are useful as tachykinin antagonists. More particularly, thecompounds of the invention are useful as neurokinin 1 (NK-1) receptorantagonists.

[0002] The present invention provides compounds of the formula (I):

[0003] wherein

[0004] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alyl;

[0005] R² is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxysubstituted by C₁₋₄alkoxy;

[0006] R³ is hydrogen, halogen or fluoroC₁₋₆alkyl;

[0007] R⁴ is hydrogen, halogen, C₁₋₆akyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined;

[0008] R⁵ is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxysubstituted by C₁₋₄alkoxy;

[0009] R⁶ represents hydrogen or a C₁₋₄alkyl group optionallysubstituted by a hydroxy group;

[0010] R⁷ represents halogen, hydroxy, C₂₋₄alkenyl, C₂₋₄alkynyl, N₃,—NR¹⁰R¹¹, —NR^(a)COR^(b), —OSO₂R^(a), —(CH₂)_(p)NR^(a)(CH₂)_(q)COOR^(b),COR^(a), COOR^(a), —N═C═O, or a five membered or six memberednitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3additional heteroatoms selected from N, O and S which heteroaromaticring is optionally substituted at any substitutable position by asubstituent selected from ═O, ═S, halogen, hydroxy, —SH, COR^(a),CO₂R^(a), -ZNR¹⁰R¹¹, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, fluoroC₁₋₄alkyl,chloroC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy or C₁₋₄alkoxy substitutedby a C₁₋₄alkoxy or hydroxyl group, and wherein said C₂₋₄alkenyl andC₂₋₄alkynyl groups are optionally substituted by a substituent selectedfrom halogen, hydroxy, N₃, —NR¹⁰R¹¹, —NR^(a)COR^(b), —OSO₂R^(a),—(CH₂)_(p)NR^(a)(CH₂)_(q)COOR^(b), COR^(a) or COOR^(a);

[0011] or R⁷ represents a C-linked nitrogen-containing ring of theformula

[0012] wherein A represents NR¹⁴ or O, and B represents a bond, CH₂,NR¹⁴ or O, wherein one or both hydrogen atoms in said CH₂ moiety may bereplaced with one or both of R¹² and R¹³, or alternatively, one of thehydrogen atoms in said CH₂ moiety together with a hydrogen atom from anadjacent carbon are replaced by a double bond;

[0013] with the proviso that when A is O, then B is NR¹⁴;

[0014] and with the further proviso that when R⁷ represents saidC-linked nitrogen-containing ring, n is zero and R⁸ is hydrogen;

[0015] R⁸ represents hydrogen, C₁₋₆alkyl, fluoroC₁₋₆allyl, hydroxy,C₁₋₆alkoxy or hydroxyC₁₋₆alkyl;

[0016] R⁹ represents hydrogen, halogen, C₁₋₆alkyl, CH₂OR^(c), oxo,CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b) are as previouslydefined and R^(c) represents hydrogen, C₁₋₆alkyl or phenyl;

[0017] R¹⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group, or R¹⁰ is a five membered or six memberednitrogen-containing heteroaromatic ring as previously defined;

[0018] R¹¹ is hydrogen or C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group;

[0019] or R¹⁰, R¹¹ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted byone or two groups selected from hydroxy, COR^(e), CO₂R^(e), C₁₋₄alkyloptionally substituted by a C₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxyoptionally substituted by a C₁₋₄alkoxy or hydroxyl group, or a fivemembered or six membered nitrogen-containing heteroaromatic ring aspreviously defined, or said heteroaliphatic ring is substituted by aspiro-fused lactone ring or a spiro-fused ring of the formula—(CH₂)_(r)O(CH₂)_(s)— (where r and s are each independently zero, 1, 2or 3 and the sum total of r and s is 3), and said heteroaliphatic ringoptionally containing a double bond, which heteroaliphatic ring mayoptionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂or a second nitrogen atom which will be part of a NH or NR^(d) moiety,where R^(d) is C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy, and where R^(e) is hydrogen, C₁₋₄alkyl or benzyl;

[0020] or R¹⁰, R¹¹ and the nitrogen atom to which they are attached forma non-aromatic azabicyclic ring system of 6 to 12 ring atoms;

[0021] or R¹⁰, R¹¹ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzenering or a five membered or six membered nitrogen-containingheteroaromatic ring optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O and S;

[0022] R¹² and R¹³ each independently represent hydrogen, hydroxy,COR^(e), CO₂R^(e), C₁₋₄alkyl optionally substituted by a C₁₋₄alkoxy orhydroxyl group, or C₁₋₄alkoxy optionally substituted by a C₁₋₄alkoxy orhydroxyl group;

[0023] or, when they are attached to the same carbon atom, R¹² and R¹³may together represent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(k)—,—CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—,—C(CH₃)₂OCH₂CH₂—, —CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—,—C(O)OC(CH₃)₂CH₂—, —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(k)—, —OC(CH₃)₂CH₂CH₂—,—OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula

[0024] or, where they are attached to adjacent carbon atoms, R¹² and R¹³may together represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹² and R¹³ maytogether form a fused benzene ring;

[0025] or, R¹² and R¹³ together form a C₁₋₂alkylene bridge across thepyrrolidine, piperidine, morpholine or piperazine ring to which they areattached;

[0026] R¹⁴ represents hydrogen, benzyl, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄allyl, or C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group;

[0027] R¹⁵ represents hydrogen, halogen, hydroxy, C₁₋₄alkyl,hydroxyC₁₋₄alkyl or fluoroC₁₋₄alkyl;

[0028] Z represents a bond, C₁₋₆alkylene or C₃₋₆cycloalkylene;

[0029] k is 1, 2 or 3;

[0030] m is 1 or 2;

[0031] n is zero, 1 or 2;

[0032] p is 1 or 2; and

[0033] q is 1 or 2;

[0034] and pharmaceutically acceptable salts thereof.

[0035] A preferred class of compounds of formula (I) is that wherein R¹is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

[0036] Another preferred class of compounds of formula (I) is thatwherein R² is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

[0037] Also preferred is the class of compounds of formula (I) whereinR³ is hydrogen, fluorine, chlorine or CF₃.

[0038] A particularly preferred class of compounds of formula (I) isthat wherein R¹ is fluorine, chlorine or CF₃.

[0039] Another particularly preferred class of compounds of formula (I)is that wherein R² is hydrogen, fluorine, chlorine or CF₃.

[0040] Also particularly preferred is the class of compounds of formula(I) wherein R³ is hydrogen, fluorine, chlorine or CF₃.

[0041] Preferably R¹ and R² are in the 3 and 5 positions of the phenylring.

[0042] More preferably R¹ is 3-fluoro or 3-CF₃.

[0043] More preferably R² is 5-fluoro or 5-CF₃.

[0044] More preferably R³ is hydrogen.

[0045] Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ ishydrogen.

[0046] A further preferred class of compound of formula (I) is thatwherein R⁴ is hydrogen or fluorine, especially hydrogen.

[0047] Another preferred class of compounds of formula (I) is thatwherein R⁵ is hydrogen, fluorine, chlorine or CF₃.

[0048] Preferably R⁴ is hydrogen or 3-fluoro, especially hydrogen, andR⁵ is hydrogen or 4-fluoro.

[0049] R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group.

[0050] Where —NR¹⁰R¹¹ is defined as a substituent R⁷ or as a substituenton a heteroaromatic ring in the definition of R⁷, then R¹⁰ may aptly bea C₁₋₄alkyl group or a C₂₋₄alkyl group substituted by a hydroxyl orC₁₋₂alkoxy group, R¹¹ may aptly be a C₁₋₄alkyl group or a C₁₋₂alkylgroup substituted by a hydroxyl or C₁₋₂alkoxy group, or R¹⁰ and R¹¹ maybe linked so that, together with the nitrogen atom to which they areattached, they form an azetidinyl, pyrrolidinyl, piperidinyl,morpholino, thiomorpholino, piperazino or piperazino group substitutedon the nitrogen atom by a C₁₋₄alkyl group or a C₂₋₄alkyl groupsubstituted by a hydroxy or C₁₋₂alkoxy group. Particularly preferredheteroaliphatic rings formed by —NR¹⁰R¹¹ are azetidine, pyrolidine,piperidine, morpholine, piperazine and N-methylpiperazine, andespecially piperidine.

[0051] Where the group NR¹⁰R¹¹ represents a heteroaliphatic ring of 4 to7 ring atoms substituted by two groups, the first substituent ispreferably selected from hydroxy, CO₂R^(e) (where R^(e) is hydrogen,methyl, ethyl or benzyl), or C₁₋₂alkyl substituted by hydroxy. Thesecond substituent is preferably a methyl group. Where two substituentsare present, said substituents are preferably attached to the samecarbon atom of the heteroaliphatic ring.

[0052] Where the group NR¹⁰R¹¹ represents a heteroaliphatic ring of 4 to7 ring atoms substituted by a spiro-fused lactone ring, particularlypreferred examples are:

[0053] Where the group NR¹⁰R¹¹ represents a heteroaliphatic ring of 4 to7 ring atoms substituted by a spiro-fused ring of the formula—(CH₂)_(r)O(CH₂)_(s)—, particularly preferred examples are:

[0054] Where the group NR¹⁰R¹¹ represents a heteroaliphatic ring of 4 to7 ring atoms and said ring contains a double bond, a particularlypreferred group is 3-pyrroline.

[0055] Where the group NR¹⁰OR¹¹ represents a non-aromatic azabicyclicring system, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include5-azabicyclo[2.1.1hexyl, 5-azabicyclo[2.2.1]heptyl,6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl,6-azabicyclo[3.2.2]nonyl, 6-azabicyclo [3.3.1]nonyl,6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.1]decyl,7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

[0056] Where the group NR¹⁰R¹¹ represents a heteroaliphatic ring of 4 to7 ring atoms to which is fused a benzene ring or a five membered or sixmembered nitrogen-containing heteroaromatic ring ring optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O and S,said heteroaromatic ring is preferably a five-membered ring, inparticular a pyrrole, imidazole or triazole ring, a nitrogen atom ofwhich is preferably included in the heteroaliphatic ring. Suitableexamples of such fused ring systems include

[0057] Particularly suitable moieties NR¹⁰R¹¹ include those whereinNR¹⁰R¹¹ is amino, methylamino, dimethylamino, diethylamino, azetidino,pyrrolidino, piperidino, morpholino and piperazino.

[0058] Where R⁷ represents an optionally substituted five orsix-membered nitrogen-containing heteroaromatic ring optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O and S,the heteroaromatic ring is selected from pyrrole, pyridine, pyrazole,imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine,pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, andtetrazole.

[0059] Preferred compounds of the present invention are those wherein R⁷is a group selected from imidazole, 1,2,3-triazole and 1,2,4-triazole.

[0060] Particularly preferred compounds of the present invention arethose wherein R⁷ is a group selected from imidazol-1-yl and1,2,4-triazol-1-yl.

[0061] Where R⁷ represents an optionally substituted five membered orsix membered nitrogen-containing heteroaromatic ring, preferredsubstituents are -ZNR¹⁰R¹¹ and C₁₋₂alkyl (especially methyl). Withreference to the group ZNR¹⁰R¹¹ defined as a substituent on aheteroaromatic ring in the definition of R⁷, Z may be a bond or alinear, branched or cyclic group. Favourably Z is a bond or contains 1to 4 carbon atoms and most favourably 1 to 2 carbon atoms. Aparticularly favourable group Z is —CH₂. In this instance, particularlysuitable moieties NR¹⁰R¹¹ include those wherein NR¹⁰R¹¹ is amino,methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino,piperidino, morpholino and piperazino. Most especially, -ZNR¹⁰R¹¹, as asubstituent on a heteroaromatic ring in the definition of R⁷, ispreferably CH₂N(CH₃)₂.

[0062] A further preferred class of compound of formula (I) is thatwherein R⁷ represents halogen (especially iodine), hydroxy, vinyl, N₃ or—OSO₂R^(a) (especially where R^(a) is methyl).

[0063] Another preferred class of compound of formula (I) is thatwherein R⁸ is hydrogen or methyl, and especially hydrogen.

[0064] Another preferred class of compounds of formula (I) is thatwherein R¹² is hydrogen, hydroxy, C₁₋₂alkyl substituted by hydroxy,C₁₋₄alkoxy (especially methoxy) or CO₂R^(e) (where R^(e) is hydrogen,methyl ethyl or benzyl).

[0065] A further preferred class of compounds of formula (I) is thatwherein R¹³ is hydrogen or C₁₋₄alkyl (especially methyl).

[0066] R¹² and R¹³ are preferably attached to the same carbon atom. Inparticular, when B represents CH₂, both hydrogen atoms in said CH₂moiety are replaced by R¹² and R¹³ forming a moiety of the formulaCR¹²R^(13.)

[0067] Where R¹² and R¹³ are attached to the same carbon atom they may,in particular, together represent —C(O)OCH₂CH₂—.

[0068] In a further preferred class of compounds of formula (I), R¹⁴preferably represents hydrogen, methyl or ethyl. Where A and B bothrepresent NR¹⁴, each R¹⁴ substituent is independently defined.

[0069] A further preferred class of compound of formula (I) is thatwherein n is 1 or 2, and especially wherein n is 1.

[0070] Another preferred class of compound of formula (I) is thatwherein R⁹ is hydrogen.

[0071] One favoured group of compounds of the present invention are ofthe formula (Ia) and pharmaceutically acceptable salts thereof:

[0072] wherein

[0073] A¹ is fluorine or CF₃;

[0074] A² is fluorine or CF₃;

[0075] A³ is fluorine or hydrogen;

[0076] A⁴ is fluorine or hydrogen, especially hydrogen;

[0077] A⁵ is methyl or hydroxymethyl; and

[0078] R⁷ and n are as defined in relation to formula (I).

[0079] When any variable occurs more than one time in formula (I) or inany substituent, its definition on each occurrence is independent of itsdefinition at every other occurrence.

[0080] As used herein, the term “alkyl” or “alkoxy” as a group or partof a group means that the group is straight or branched. Examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups includemethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

[0081] As used herein, the terms “fluoroC₁₋₆alkyl” and fluoroC₁₋₆alkoxy”means a C₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (inparticular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms.Similarly, the term “fluoroC₁₋₄alkyl” means a C₁₋₄alkyl group in whichone or more (in particular 1 to 3) hydrogen atoms have been replaced byfluorine atoms. Particularly preferred are fluoroC₁₋₃alkyl andfluoroC₁₋₃alkoxy groups, for example, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃,OCF₃, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ andOCH₂CF₃.

[0082] The cycloalkyl groups referred to herein may represent, forexample, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

[0083] Similarly cycloalkoxy groups referred to herein may represent,for example, cyclopropoxy or cyclobutoxy.

[0084] As used herein, the terms “alkenyl” and “alkynyl” as a group orpart of a group means that the group is straight or branched. Examplesof suitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

[0085] When used herein the term “halogen” means fluorine, chlorine,bromine and iodine. The most apt halogens are fluorine and chlorine ofwhich fluorine is preferred, unless otherwise stated.

[0086] Specific compounds within the scope of this invention include:

[0087] [(2SR, 3SR,4SR)-2-({(1RS)-1-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine;

[0088] [(2SR, 3SR,4SR)-2-({(1SR)-1-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine;

[0089] [(2SR, 3SR,4SR)-2-({(1SR)-1-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]-N,N-dimethylmethanamine;

[0090] (2SR, 3SR, 4SR, 2[(1′)]RS)2-(4-aminomethyl-3-phenyl-tetrahydro-furan-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol;

[0091] (2SR, 3SR, 4SR, 2[(1′)]SR)2-(4-aminomethyl-3-phenyl-tetrahydrofaran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol;

[0092] (2RS)-2-[3,5-bis(trifluoromethyl)phenyl]-2-({(2SR, 3SR,4SR)-4-[(N,N-dimethylamino)methyl]-3-phenyltetrahydro-2-faranyl}oxy)ethanol;

[0093] [(2RS, 3RS,4SR)-2-({(1SR)-1-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine;

[0094] [(2RS, 3RS,4SR)-2-({(1RS)-1-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4faranyl]methanamine;

[0095] [(2RS, 3RS,4SR)-5-({(1RS)-1-[3,5-bis(trifluoromethyl)phenyl]-ethylsoxy)-3-phenyltetrahydro4-furanyl]-N,N-dimethylmethanamine;

[0096] (2RS, 3SR, 4SR, 2[(1′)]RS)2-(4-aminomethyl-3-phenyl-tetrahydrofaran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol;

[0097] (2RS, 3SR, 4SR, 2[(1′)]SR)2-(4-aminomethyl-3-phenyl-tetrahydrofuran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol;

[0098] and pharmaceutically acceptable salts thereof.

[0099] In a further aspect of the present invention, the compounds offormula (I) may be prepared in the form of a pharmaceutically acceptablesalt, especially an acid addition salt.

[0100] For use in medicine, the salts of the compounds of formula (I)will be non-toxic pharmaceutically acceptable salts. Other salts may,however, be useful in the preparation of the compounds according to theinvention or of their non-toxic pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts of the compounds of thisinvention include acid addition salts which may, for example, be formedby mixing a solution of the compound according to the invention with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acidor sulphuric acid. Salts of amine groups may also comprise quaternaryammonium salts in which the amino nitrogen atom carries a suitableorganic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includemetal salts such as alkali metal salts, e.g. sodium or potassium salts;and alkaline earth metal salts, e.g. calcium or magnesium salts.

[0101] The salts may be formed by conventional means, such as byreacting the free base form of the product with one or more equivalentsof the appropriate acid in a solvent or medium in which the salt isinsoluble, or in a solvent such as water which is removed in vacuo or byfreeze drying or by exchanging the anions of an existing salt foranother anion on a suitable ion exchange resin.

[0102] The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

[0103] A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

[0104] The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

[0105] The compounds according to the invention have at least threeasymmetric centres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

[0106] The preferred compounds of the formula (I) and (Ia) will have thestereochemistry of the 2-, 3-, 4 and 8-positions as shown in formulae(Ib) and (Ic)

[0107] It will be appreciated that the preferred definitions of thevarious substituents recited herein may be taken alone or in combinationand, unless otherwise stated, apply to the generic formula for compoundsof the present invention as well as to the preferred classes of compoundrepresented by formula (Ia), formula (Ib) and formula (Ic).

[0108] The present invention further provides pharmaceuticalcompositions comprising one or more compounds of formula (I) inassociation with a pharmaceutically acceptable carrier or excipient.

[0109] Preferably the compositions according to the invention are inunit dosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.Oral compositions such as tablets, pills, capsules or wafers areparticularly preferred.

[0110] A more detailed description of pharmaceutical compositions thatare suitable for the formulation of compounds of the present inventionis disclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see in particular, column 8, line 50to column 10, line 4).

[0111] The present invention further provides a process for thepreparation of a pharmaceutical composition comprising a compound offormula (I), which process comprises bringing a compound of formula (I)into association with a pharmaceutically acceptable carrier orexcipient.

[0112] The compounds of formula (I) are of value in the treatment of awide variety of clinical conditions which are characterised by thepresence of an excess of tachykinin, in particular substance P,activity. A comprehensive listing of clinical conditions, uses andmethods of treatment for which the compounds of the present inventionwill be useful is disclosed in U.S. Pat. No. 6,071,927, the content ofwhich is incorporated herein by reference (see, in particular, column10, line 14 to column 22, line 18).

[0113] In particular, the compounds of the present invention are usefulin the treatment of a variety of disorders of the central nervoussystem. Such disorders include mood disorders, such as depression ormore particularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; and anxiety disorders, such as panic disorder withor without agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders.

[0114] The compounds of the present invention are also particularlyuseful in the treatment of nociception and pain. Diseases and conditionsin which pain predominates, include soft tissue and peripheral damage,such as acute trauma, osteoarthritis, rheumatoid arthritis,musculo-skeletal pain, particularly after trauma, spinal pain,myofascial pain syndromes, headache, migraine, episiotomy pain, andburns.

[0115] The compounds of the present invention are also particularlyuseful in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm; inthe treatment of inflammatory diseases such as inflammatory boweldisease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis,pruritis and sunburn; and in the treatment of allergic disorders such aseczema and rhinitis.

[0116] The compounds of the present invention are also particularlyuseful in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as ulcerativecolitis, Crohn's disease and irritable bowel syndrome.

[0117] The compounds of the present invention are also particularlyuseful in the treatment of emesis, including acute, delayed oranticipatory emesis, such as emesis induced by chemotherapy, radiation,toxins, pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. Most especially, the compounds offormula (I) are of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents, including those routinely used incancer chemotherapy; by radiation including radiation therapy such as inthe treatment of cancer; and in the treatment of post-operative nauseaand vomiting.

[0118] The excellent pharmacological profile of the compounds of thepresent invention offers the opportunity for their use in therapy at lowdoses thereby minimising the risk of unwanted side effects.

[0119] In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

[0120] For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

[0121] In the treatment of emesis, a suitable dosage level is about0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day,and especially 0.01 to 3 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

[0122] In the treatment of psychiatric disorders, a suitable dosagelevel is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds maybe administered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

[0123] It will be appreciated that the amount of a compound of formula(I) required for use in any treatment will vary not only with theparticular compounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

[0124] According to a general process (A), compounds of formula (I), inwhich n is 1, may be prepared by the reaction of a compound of formula(II)

[0125] wherein LG is a suitable leaving group such as an alkyl- orarylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom(e.g. bromine, chlorine or iodine); with an appropriate amine of theformula HNR¹⁰R¹¹, or a heteroaromatic compound suitable for the additionof a five or six-membered nitrogen containing heteroaromatic ring asdefined in relation to formula (I), or an azide such as sodium azide.

[0126] In each case, the reaction is preferably effected at an elevatedtemperature, for example, between 40° C. and 80° C., especially between50° C. and 60° C. The reaction with a heteroaromatic compound ispreferably effected in the presence of a suitable organic solvent suchas dimethylformamide. The reaction with an azide is preferably effectedin the presence of dimethylsulfoxide.

[0127] A particularly preferred compound of formula (II) is that whereinthe group LG is mesylate—i.e. a compound of formula (I) in which R⁷ isthe group —OSO₂CH₃.

[0128] According to another general process (B), compounds of formula(I), in which R⁷ is hydroxy and n is 1 or 2, may be prepared by theinterconversion of a corresponding compound of formula (I) in which n iszero and R⁷ is vinyl, hereinafter referred to as formula (III)

[0129] by reaction with ozone, followed by a reaction with a reducingagent such as sodium borohydride (n is 1), or by reaction with areducing agent such as borane.tetrahydrofuran complex, followed byhydrogen peroxide in the presence of a base such as sodium hydroxide.

[0130] According to another general process (C), compounds of formula(I) may be prepared by the reaction of a compound of formula (IV) with acompound of formula (V)

[0131] preferably in the presence of a resin catalyst such as Amberlyst™15, and 3 Angstrom molecular sieves.

[0132] The reaction is conveniently effected in a suitable solvent suchas a halogenated hydrocarbon, for example, dichloromethane, convenientlyat room temperature.

[0133] According to another general process (D), compounds of formula(I), in which R⁶ is either methyl or hydroxymethyl, may be prepared bythe reaction of a compound of formula (VI)

[0134] wherein R^(7a) is as defined for R⁷ in relation to formula (I)or, more preferably, is a precursor therefor; under either:

[0135] (a) (where R⁶ is methyl) catalytic hydrogenation conditions (e.g.H₂, Pd(OH)₂ on carbon) in a suitable solvent such as an ester, forexample, ethyl acetate; or

[0136] (b) (where R⁶ is hydroxymethyl) reducing conditions (e.g. boraneor BH₃.TBF) followed by treatment with hydrogen peroxide and a base suchas sodium hydroxide, conveniently in a solvent such as an ether, forexample, tetrahydrofuran.

[0137] Where R^(7a) is a precursor group (such as a TBDMS-protectedhydroxyl group) deprotection is conveniently effected by treatment withan organic acid such as tetrabutylammonium fluoride.

[0138] According to another general process (E), compounds of formula(I) in which R⁷ is a C-linked nitrogen-containing ring wherein A is NR¹⁴and B is CH₂ may be prepared by the reaction of a compound of formula(XII)

[0139] in the presence of a suitable catalyst, and if desired reducingthe tetrahydropyridinyl moiety, and also if desired removing orreplacing the benzyl moiety.

[0140] Suitable catalysts of use in this reaction include any catalystor multicomponent catalyst system that initiates olefin metathesis.Preferred catalysts are single component metal carbene complexes.Particularly preferred catalysts include:

[0141] An especially preferred catalyst of use in the present inventionis RuCl₂(PCy₃)₂=CHPh, also referred to as Grubbs' catalyst. Thesecatalysts and their use is described, for instance, in the followingliterature:

[0142] Bazan et al., J. Am. Chem. Soc., 1991, 113, 6899 and referencescited therein.

[0143] Nguyen et al., J. Am. Chem. Soc., 1992, 114, 3974.

[0144] Nguyen and Grubbs, J. Organomet. Chem., 1995,497, 195

[0145] Schwab et al., Angew. Chem. Int. Ed. Eng., 1995, 34, 2039.

[0146] Schwab et al., J. Am. Chem. Soc., 1996, 118, 100.

[0147] Grubbs and Chang, Tetrahedron, 1998, 54, 4413.

[0148] Suitable organic solvents of use in the reaction includehalogenated hydrocarbons, such as dichloromethane or chloroform.

[0149] The reaction is conveniently effected at room temperature andpressure, for example at about 20° C.

[0150] Reduction of the tetrahydropyridinyl moiety may be effected byconventional methodology, for example, by catalytic hydrogenation in thepresence of a suitable catalyst such as palladium on carbon, in asuitable solvent such as an alcohol, for example, methanol. Theseconditions will also conveniently remove the benzyl moiety (R¹⁴) whichmay be replaced using conventional methodology.

[0151] According to another general process (F), compounds of formula(I) in which R⁷ is a C-linked nitrogen-containing ring wherein A is NR¹⁴and B is a bond may be prepared by the reaction of a compound of formula(XIII)

[0152] under reducing conditions, for instance, in the presence ofborane or borane.tetrahydrofuran complex, followed by treatment withhydrogen peroxide and a base such as sodium hydroxide. The reaction isconveniently effected in a solvent such as an ether, for example,tetrahydrofiiran.

[0153] If desired, the benzyl moiety (R¹⁴) may be removed as describedabove.

[0154] According to another general process (G), compounds of formula(I) in which R⁷ is a C-linked nitrogen-containing ring wherein A is NR¹⁴and B is O may be prepared by the reaction of a compound of formula(XIV)

[0155] with an amine of the formula R¹⁴NH₂, followed by reduction of theketo function using a suitable reducing agent such as a borohydride, forexample sodium cyanoborohydride. The reduction is conveniently effectedin a solvent such as an ether, for example, tetrahydrofuran.

[0156] According to another general process (H), compounds of formula(I) in which R⁷ is a C-linked nitrogen-containing ring wherein A is Oand B is NR¹⁴ may be prepared by the reaction of a compound of formula(XV)

[0157] under suitable dehydrating conditions, for example, usingtriphenylphosphine and diethylazodicarboxylate in a suitable solventsuch as tetrahydrofuran, at an elevated temperature such as at reflux,or alternatively using methanesulfonyl chloride or benzenesulfonylchloride in pyridine or triethylamine, in a suitable organic solventsuch as dichloromethane, conveniently at a temperature between roomtemperature and 80° C.

[0158] Further details of suitable procedures will be found in theaccompanying Examples.

[0159] Compounds of formula (II) may be prepared by conventional methodsfrom, for example, a corresponding compound of formula (I) in which R⁷is a hydroxyl group. Thus, for example, when LG is a mesylate group acorresponding compound of formula (I) in which R⁷ is hydroxyl may bereacted with methanesulfonyl chloride in the presence of a base, such astriethylamine. The reaction is conveniently effected in a solvent suchas a halogenated hydrocarbon, for example, dichloromethane.

[0160] Compounds of formula (III) may be prepared, for example, by themethod of general process (C), above

[0161] Compounds of formula (IV) may be prepared by the reduction of acompound of formula (VII)

[0162] using conventional conditions such as sodium borohydride in thepresence of a transition metal catalyst such as cerium chloridehexahydrate, in a solvent such as alcohol, for example, ethanol; orusing DiBAL in a solvent such as a halogenated hydrocarbon, for example,dichloromethane.

[0163] Compounds of formula (VII) in which R⁷ is vinyl, R⁸ is hydrogenand n is 1 may be prepared from a compound of formula (VI)

[0164] by reaction with a vinyl Grignard reagent such as vinylMgBr,preferably in the presence of copper(I)iodide, and a suitable solventsuch as an ether, for example, tetrahydrofuran. This reaction iseffected at reduced temperature, for example, below −40° C. andpreferably at −78° C.

[0165] Compounds of formula (VI) may be prepared by the reaction of acompound of formula (X)

[0166] with dimethyltitanocene in a solvent such as toluene, pyridine ortetrahydrofuran, or a mixture thereof. Compounds of formula (X) may beprepared by the reaction of a compound of formula (VII) withL-Selectride™ (lithium tri-sec-butylborohydride) followed by treatmentwith a compound of formula (XI)

[0167] wherein Hal is a halogen atom, preferably chlorine.

[0168] Compounds of formula (XII) may be prepared from a compound offormula (XIII) above, by N-alkylation with an allyl halide, for example,allyl bromide. The reaction is preferably effected in the presence of aninorganic base such as potassium carbonate and a suitable solvent such adimethylformamide. The reaction is conveniently effected at atemperature between room temperature and 100° C.

[0169] Compounds of formula (XIII) may be prepared from a compound offormula (XVI)

[0170] by reaction with benzylamine in a suitable solvent such as ahalogenated hydrocarbon, for example, dichloromethane. Followingbasification, using for example basic alumina, the reaction mixture isfiltered, evaporated and the residue dissolved in a suitable solventsuch as an ether, for example, tetrahydrofuran. Reaction with a suitablealkylating reagent such as a Grignard reagent, for example, allylmagnesium bromide, in the presence of a suitable solvent such as anether, for example, diethyl ether, affords the compound of formula (ME).

[0171] Compounds of formula (XVI) may be prepared from a compound offormula (III) by an ozonolysis reaction, using ozone at a lowtemperature, for example, between −60° C. and −100° C., in a suitablesolvent such as a halogenated hydrocarbon, for example, dichloromethane,or an alcohol, for example, methanol, or a mixture thereof. Theintermediate ozonide thus formed need not be isolated but instead isdecomposed using a suitable reducing agent, for example, dimethylsulfide, trimethyl phosphite or thiourea.

[0172] Compounds of formula (XIV) may be prepared from a compound offormula (XVII)

[0173] by reaction with allyl alcohol in the presence of a suitablereducing reagent, such as a hydride, for example sodium hydride, in asuitable solvent such as an ether, for example tetrahydrofuran, at anelevated temperature, for example, between 60° C. and 100° C., followedin a second step by an oxidation reaction, for example using a mildoxidizing reagent such as Dess-Martin periodinane, in a suitable solventsuch as a halogenated hydrocarbon, for example dichloromethane,conveniently at room temperature.

[0174] Compounds of formula (XVII) may be prepared from a compound offormula (III) by an epoxidization reaction using a peracid, for example,m-chloroperbenzoic acid. The reaction is effected in a solvent such as ahalogenated hydrocarbon, for example, dichloromethane, conveniently atroom temperature.

[0175] Compounds of formula (XV) may be prepared from a compound offormula (XVII) by reaction with a suitable amine of the formulaR¹⁴NHCH₂CH₂OH. The reaction is conveniently effected in a solvent suchas an alcohol, for example methanol, at an elevated temperature, forexample at the reflux temperature of the solvent.

[0176] Compounds of formula (V), (VIII) and (XI) are either knowncompounds or may be prepared by methods analogous to those describedherein.

[0177] It will be appreciated that the general methodology describedabove may be adapted, using methods that are readily apparent to one ofordinary skill in the art, in order to prepare further compounds of thepresent invention.

[0178] During any of the above synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0179] The exemplified compounds of this invention were tested by themethods set out at pages 36 to 39 of International Patent SpecificationNo. WO 93/01165. The compounds were found to be active with IC₅₀ at theNK₁ receptor of less than 100 nM on said test method.

[0180] The following non-limiting Examples serve to illustrate thepreparation of compounds of the present invention:

DESCRIPTION 1

[0181] 3-Iodo-3-phenyl-prop-2-en-1-ol

[0182] Red-Al™ (3.4M in toluene, 33 ml) was dissolved in diethyl ether(100 ml) and cooled to −10° C. to which 3-phenyl-2-propyn-1-ol (10 g,0.076 mol) dissolved in diethyl ether (10 ml) was added dropwise,causing the solution to turn a dark red/brown colour. The reaction wasstirred for 1 hour. The solution was cooled to −78° C. and iodinemonochloride (1.0M solution in dichloromethane, 114 ml) was addedcausing the solution to turn a dark brown colour. The mixture wasallowed to warm to room temperature and stirred for 1 hour. A 10%solution of potassium sodium tartaric acid (800 ml) was added, producinga white precipitate, this was removed by filtration and the filtrate wasextracted with diethyl ether (3×75 ml). The combined organic extractswere washed with sodium thiosulphate (5×60 ml), brine, dried (MgSO₄) andthe solvent removed in vacuo to afford the crude title compound as alight brown oil (19.5 g, 95%).

[0183]¹H NMR (250 MHz, CDCl₃) δ1.76 (1H, t, J 5.7 Hz), 4.39 (2H, t, J5.6 Hz), 6.25 (1H, t, J 5.8 Hz), 7.10-7.50 (5H, m).

DESCRIPTION 2

[0184] 3-phenyl-5H-furan-2-one

[0185] 3-Iodo-3-phenyl-prop-2-en-1-ol (Description 1; 1 g, 3.8 mM)wasdissolved in tetrahydrofuiran (20 ml) and Hunig's base (2.67 ml, 15.4mM) and degassed using a Firestone valve (×3). Carbon monoxide wasbubbled through the solution for 10 minutes after whichtris(dibenzylideneacetone)dipalladium (141mg; 4 mol %) and 1,4bis(diphenylphosphino) butane (65 mg; 4 mol %) were added. The reactionwas heated at 50° C. under an atmosphere of carbon monoxide. After 2hours, when the reaction was 50% complete, an extra addition of thepalladium source and phosphine ligand were made. After a further 2 hoursthe reaction was cooled, filtered, the solvent removed in vacuo and theresidue was dispersed between ethyl acetate and water. The aqueous layerwas extracted with ethyl acetate (2×40 ml), the combined organic layerswere washed with brine, dried over MgSO₄ and the solvent removed invacuo. Purification was carried out by silica chromatography eluting inincreasing concentrations of ethyl acetate in hexane (0-15%) to affordthe title compound as a tan-coloured solid (0.56 g, yield 91%).

DESCRIPTION 3

[0186] 5-Oxo4-phenyl-tetrahydrofuran-3-carbonitrile

[0187] 3-Phenyl-5H-furan-2-one (Description 2; 4.5 g, 0.028 mol), andacetone cyanohydrin (3.06 ml) were dissolved in CH₃CN (80 ml) and cooledto −0° C. Tetramethylguanidine (3.5 ml) was added dropwise over 15minutes and the reaction left to stand for a further 15 minutes. 0.5MHCl (100 ml) was added and the reaction mixture de-colourised and theproduct extracted with ethyl acetate (2×40ml), washed with brine(2×30ml) and dried over MgSO₄. The solvent was removed in vacuo toafford a brown oil which was a mixture of the cis and trans isomers.Purification was carried out using flash column chromatography on silicagel eluting in increasing concentrations of ethyl acetate in hexane(0-60%) to yield the title compound (2.93 g, 56%). The only isolatedproduct from the column was the more thermodynamically stable transisomer.

[0188]¹H-NMR (250 MHz, CDCl₃) δ trans isomer: 3.54 (1H, ddd, J 10.9 Hz,9.6 Hz, 8.1 Hz), 4.10 (1H, d, J 11.0 Hz), 4.43 (1H, t, J 9.4 Hz), 4.69(1H, t, J 9.2 Hz), 7.40 (5H, m).

[0189]¹H-NMR (250 MHz, CDCl₃) δ cis isomer: 3.87 (1H, m), 4.10 (1H, d, J2.3 Hz), 4.56 (2H, d, J 6.0 Hz), 7.41 (5H, m).

DESCRIPTION 4

[0190] (5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl)carbamic acidtert-butyl ester

[0191] 5-Oxo-4-phenyl-tetrahydrofuiran-3-carbonitrile (Description 3;7.1 g, 0.038 mol) was added to di-tert-butyldicarbonate (24 g), platinumdioxide catalyst (1.4 g), ethyl acetate (150 ml) and acetic acid (20 ml)and shaken under an atmosphere of hydrogen (50 psi) for 24 hours. Thecatalyst was removed by filtration, solvent removed in vacuo and theresidue was purified using flash column chromatography on silica geleluting in increasing concentrations of ethyl acetate in hexane (5-50%)to give the title compound as a brown oil (2.16 g).

DESCRIPTION 5

[0192] (3RS, 4RS) 4-Aminomethyl-3-phenyl-dihydrofaran-2-one

[0193] (5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl)carbamic acidtert-butyl ester (Description 4; 2.16 g, 7.4 mmol) was dissolved indichloromethane (10 ml), cooled to 0° C., trifluoroacetic acid (1 ml)was added and the reaction was left to stand for 20 minutes to warm toroom temperature. TLC showed the reaction to be incomplete so extratrifluoroacetic acid (1 ml) was added and the reaction was left for afurther 30 minutes. The solvent was removed in vacuo and the residue wasdispersed between ethyl acetate and saturate potassium carbonatesolution. The aqueous layer was extracted with ethyl acetate (2×30 ml),the combined organic layers were washed with brine, dried over MgSO₄,filtered and evaporated to dryness. Purification was carried out byflash column chromatography on silica gel eluting in increasingconcentrations of methanol in dichloromethane and 0.2% ammonia (1-10%)to afford the title compound (2.15 g).

[0194] m/z (ES⁺) 191 (M+H, 100%).

DESCRIPTION 6

[0195] (3RS, 4RS)4-[(N,N-Dibenzylamino)-methyl]-3-phenyl-dihydrofuran-2-one

[0196] (3RS, 4RS) 4-Aniinomethyl-3-phenyl-dihydrofuran-2-one (2.15 g,0.011 mol) was added to potassium carbonate (15.5 g), benzyl bromide(6.69 ml) and dimethylformamide (10 ml) and stirred for 3 hours at 50°C. dimethylformamide was removed in vacuo and the reaction was dispersedbetween ethyl acetate (40 ml) and water (60 ml), the aqueous phase waswashed with ethyl acetate (2×30ml) and the organic layers were combinedand washed with brine solution (100 ml) and dried over MgSO₄. Thesolvent was removed in vacuo and purified by flash column chromatographyon silica gel and eluting in increasing concentrations of ethyl aceatein hexane (5-50%) to give the title compound (1.15 g, 46%).

[0197]¹H-NMR (250 MHz, CDCl₃) δ2.57 (2H, dd, J 6.1 Hz, 2.7 Hz), 2.86(1H, m), 3.20 (1H, d, J 13.5 Hz), 3.35 (2H, d, J 13.4 Hz), 3.63 (2H, d,J 13.3 Hz), 3.83 (1H, t, J 8.9 Hz), 4.55 (1H, t, J 7.6 Hz). mlz (ES⁺)371 (M+H, 100%).

[0198] (a) (2SR, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester; and

[0199] (b) (2RS, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester

[0200] (3RS, 4RS)4-[N,N-Dibenzylamino)-methyl]-3-phenyl-dihydrofuran-2-one (Description6; 1.53 g, 4 mmol) was dissolved in tetrahydrofuran (15 ml) under anatmosphere of nitrogen and cooled to −78° C. LSelectride™ (8.25 ml) wasadded dropwise and the reaction was left to stand for 30 minutes.Further L-Selectride™ (1.65 ml) was added,3,5-bis-trifluoromethyl-benzoyl chloride (1.86 ml) was added dropwiseand the solution was left to stand for 16 hours at −78° C. Further3,5-bis-trifluoromethyl-benzoyl chloride (0.372 ml) was added and thereaction was warmed to room temperature for 20 minutes. The reaction wasthen quenched with saturated sodium carbonate (400 ml), dispersedbetween ethyl acetate (100 ml) and the aqueous layers washed with ethylacetate (3×50 ml). The organic extracts were combined and dried overMgSO₄. The solvent was removed in vacuo and purified by flash columnchromatography on silica gel and eluting in increasing concentrations ofethyl acetate in hexane (0-20%) to yield the title compounds. Fastereluting isomer (a) (2SR, 3SR, 4SR) (0.8 g, yield 32%).

[0201]¹H-NMR (360 MHz, CDCl₃) δ2.40-2.56 (1H, m), 2.61 (1H, dd, J 8.9Hz, 2.4 Hz), 3.14 (2H, br s), 3.43 (2H, d, J 13.4 Hz), 3.67 (2H, d, J13.4 Hz), 3.71 (1H, t, J 8.0 Hz), 4.47 (1H, t, J 7.9 Hz), 6.38 (1H, d, J4.1 Hz), 7.21-7.33 (15H, m), 7.98 (1H, s), 8.17 (2H, s).

[0202] Slower eluting isomer (b) (2RS, 3SR, 4SR) (0.32 g, yield 13%).

[0203]¹H-NMR (360 MHz, CDCl₃) δ2.63 (1H, d, J 8.4 Hz), 2.65 (1H, d, J4.8 Hz), 2.78 (1H, m), 3.22 (1H, dd, J 4.1 Hz, 2.0 Hz), 3.48 (4H, dd, J26 Hz, 13.5 Hz), 3.83 (1H, t, J 8.5 Hz), 4.47 (1H, t, J 8.4 Hz), 6.34(1H, d, J 2.2 Hz), 7.10-7.38 (15H, m), 8.06 (1H, s), 8.30 (2H, s).

DESCRIPTION 8

[0204] (2SR, 3SR, 4SR)N,N-Dibenzyl-{5-[1-(3,5-bis(trifluoromethyl)-phenyl)vinyloxy]-4-phenyl-tetrahydrofaran-3-ylmethyl}amine

[0205] (2SR, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid4[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester(Description 7(a); 1.03 g, 1.7 mmol) was azeotroped withtetrahydrofiaran (2×10 ml), dissolved in tetrahydrofuran (15 ml) anddegassed with Firestone™ valve (×3). Bis(cyclopentadiene) titaniumdimethyl (1.8 ml, 2.8M in toluene) was added and the mixture was heatedto 60° C. in the dark. Further bis(cyclopentadiene) titanium dimethyl (1ml) was added and the reaction was left to stand for 18 hours. Thereaction was quenched with a slurry of sodium carbonate (4 g), water(2.5 ml) and methanol (50 ml), which caused it to turn yellow, and thereaction was left to stand at 40° C. for 16 hours under nitrogen. Thesolid was removed by filtration and the solvent removed in vacuo toafford a yellow solid. The solid was dispersed between water (50 ml) andethyl acetate (40 ml), the aqueous layer was washed with ethyl acetate(3×20 ml) and brine (1×50 ml), and dried over MgSO₄. The solvent wasremoved in vacuo and the product purified by flash column chromatographyon silica gel and eluting in increasing concentrations ofdichloromethane in hexane (10-100%) to give the title compound (299 mg,yield 29%).

[0206]¹H-NMR (360 MHz, CDCl₃) δ3.14 (1H, dd, J 4.7 Hz, 2.3 Hz), 3.37(2H, dd, J 22.4 Hz, 13.5 Hz), 3.49 (1H, m), 3.59 (2H, d, J 13.6 Hz),3.76 (2H, d, J 13.5 Hz), 3.75 (1H, t, J 8.8 Hz), 4.40 (1H, t, J 2.3 Hz),4.62 (1H d, J 3.2 Hz), 4.84 (1H, d, J 3.1 Hz), 6.69 (1H, d, J 1.4 Hz),7.11-7.37 (15H, m), 7.78 (1H, s), 7.88 (1H, s). m/z (ES⁺) 611 (M+H,44%).

DESCRIPTION 9

[0207]

[0208] (a) (2SR, 3SR, 4SR, 2[(1′)]SR)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol;and

[0209] (b) (2SR, 3SR, 4R, 2[(1′)]RS)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol

[0210] (2SR, 3SR, 4SR)Dibenzyl-{5-[1-(3,5-bis(trifluoromethyl)phenyl)vinyloxy]-4-phenyl-tetrahydrofuran-3-ylmethyl}amine(Description 8; 299 mg, 49 mmol) was azeotroped in tetrahydrofuran (3×1ml), dissolved in tetrahydrofuran (10 ml) and cooled to −10° C.Borane-THF (1.47 ml, 1.0M in THF) was added dropwise and the reactionleft to stand for 6 hours at room temperature. The mixture was quenchedwith a solution of sodium hydroxide (1.85 ml, 2M) and hydrogen peroxide(30 ml) at −10° C. and left to stand for 45 minutes. The mixture wasthen dispersed between ethyl acetate (20 ml) and water (40 ml) and thewater layer was washed with ethyl acetate (2×15 ml). The organicextracts were combined and washed with brine (1×30 ml) and dried overMgSO₄. The solvent was removed in vacuo and the residue purified byflash column chromatography on silica gel and eluting in increasingconcentrations of ethyl acetate in hexane (2.5-50%) to give the titlecompounds.

[0211] Slower eluting isomer (a) (2SR, 3SR, 4SR, 2[(1′)]RS) (53 mg,yield 17%).

[0212]¹H-NMR (360 MHz, CDCl₃) δ2.59 (1H, d, J 7.5 Hz), 2.63-2.66 (1H,m), 2.71 (1H, d, J 7.3 Hz), 2.99 (1H, dd, J 7.0 Hz, 3.0 Hz), 3.38 (1H,d, J 13.4 Hz), 3.41-3.47 (1H, m), 3.53 (2H, d, J 13.1 Hz), 3.58 (2H, d,J 13.5 Hz), 3.74 (1H, t, J 8.4 Hz), 4.36 (1H, t, J 7.6 Hz), 4.68 (1H,dd, J 7.5 Hz, 3.1 Hz), 4.86 (1H, d, J 3.0 Hz), 7.01-7.32 (15H, m), 7.59(2H, s), 7.72 (1H, s).

[0213] Faster eluting isomer (b) (2SR, 3SR, 4SR, 2[(1′)]SR) (33 mg,yield 11%).

[0214]¹H-NMR (360 MHz, CDCl₃) δ1.78 (1H, br d), 2.42 (1H, dd, J 12.1 Hz,7.2 Hz), 2.56-2.61 (1H, m), 2.70 (1H, dd, J 12.1 Hz, 7.5 Hz), 3.10 (1H,dd, J 6.1 Hz, 2.3 Hz), 3.25 (iH, t, J 8.4 Hz), 3.41 (2H, d, J 13.4 Hz),3.38-3.46 (1H, m), 3.52 (2H, d, J 13.4 Hz), 3.47-3.55 (1H, m), 4.09 (1H,t, J ^(8.1)Hz), 4.54 (1H, dd, J 7.5 Hz, 3.7 Hz), 5.15 (1H, d, J 2.4 Hz),7.18-7.35 (15H, m), 7.63 (2H, s), 7.78 (1H, s).

DESCRIPTION 10

[0215] (2RS, 3SR, 4SR)N,N-Dibenzyl-{5-[1-(3,5-bis(trifiluoromethyl)-phenyl)vinyloxy]-4phenyl-tetrahydrofuran-3-ylmethyl}amine

[0216] (2RS, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester(Description 7(b); 0.64 g) was used treated according to the proceduredescribed in Description 8. Purification was carried out by flash columnchromatography on silica gel and eluting in increasing concentrations ofethyl acetate in hexane (0-10%) to give the title compound (0.32 g,50%). m/z 612 (M+H, 100).

[0217] (a) (2RS, 3SR,4SR, 2[(1′)]RS)2-(3,5-Bis(trifluorometthyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy)-ethanol;and

[0218] (b) (2RS, 3SR, 4SR, 2[(1′)]SR)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylanino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol

[0219] (2RS, 3SR, 4SR)N,N-Dibenzyl-{5-[1-(3,5-bis(trifluoromethyl)phenyl)-vinyloxyl]-4phenyl-tetrahydrofaran-3-ylmethyl}amine(Description 10; 0.129 g) was hydroborated using the method described inDescription 9. Purification was carried out by flash silicachromatography eluting with increasing concentrations of ethyl acetate(0-20%) in hexane.

[0220] Faster eluting isomer (a) (2RS, 3SR, 4SR, 2[(1′)]RS) (23.7 mg,yield 18%).

[0221]¹H-NMR (360 MHz, CDCl₃) δ1.21(1H, dd, J 9.7 Hz, 4.0 Hz), 2.41(1H,dd, J 12.7 Hz, 9.7 Hz), 2.53 (1H, dd, J 12.7 Hz, 4.7 Hz), 2.90 (1H, dd,J 11.2 Hz, 4.6 Hz), 3.12-3.28 (1H, m), 3.30-3.52 (5H, m), 3.64 (2H, d, J13.4 Hz), 4.12 (11H, t, J 8.5 Hz), 4.50 (1H, dd, J 8.0 Hz, 3.5 Hz), 5.11(1H, d, J 4.7 Hz), 7.10-7.44 (15H, m), 7.71 (2H, s), 7.79 (1H, s).

[0222] Slower eluting isomer (b) (2RS, 3SR, 4SR, 2[(1′)]SR) (37 mg,yield 28%).

[0223]¹H-NMR (360 MHz, CDCl₃) δ2.43 (1H, dd, J 12.7 Hz, 9.9 Hz),2.53(1H, 12.7 Hz, 4.6 Hz), 2.85(1H, dd, J 11.3 Hz, 4.8 Hz), 3.01 (1H,dd, J 9.1 Hz, 3.6 Hz), 3.11-3.24 (1H, m), 3.37 (2H, d, J 13.5 Hz),3.48-3.74 (5H, m), 4.42 (1H, t, J 8.4 Hz), 4.69 (1H, dd, J 7.6 Hz, 3.0Hz), 4.92(11, d, J 4.8 Hz), 7.16-7.20 (17H, m), 7.66 (1H, s).

[0224] (a) [(2SR, 3SR,4SR)-2-({(1RS)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine;and

[0225] (b) [(2SR, 3SR,4SR)-2-({(1SR)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine

[0226] (2SR, 3SR, 4SR)N,N-Dibenzyl-{5-[1-(3,5-bis(trifluoromethyl)phenyl)-vinyloxy]-4-phenyl-tetrahydrofuran-3-ylmethyl}amine(Description 8; 0.25 g) was dissolved in methanol (20 ml), ammoniumformate (130 mg) was added and the mixture degassed with nitrogen for 10minutes. 10% palladium on carbon (80 mg) was added heated at reflux for3 hours. The reaction was filtered and evaporated to dryness in vacuoand purification was carried out by flash chromatography elution inincreasing concentrations (0-2%) methanol in dichloromethane with 0.2%ammonia.

[0227] Faster eluting isomer (a) (2SR, 3SR, 4SR, 2[(1′)RS]) (43 mg,yield 24%).

[0228]¹H-NMR (250 MHz, CDCl₃) δ1.40 (3H, d, J 6.6 Hz), 2.29-2.47 (1H,m), 2.80 (1H, dd, J 12.5 Hz, 7.8 Hz), 2.95 (1H, dd, J 12.5 Hz, 6.1 Hz),3.11 (1H, dd, J 7.0 Hz, 2.4 Hz), 3.58 (1H, t, J 8.7 Hz), 4.16 (1H, t, J8.1 Hz), 4.80 (1H, q, J 6.5 Hz), 5.25 (1H, d, J 2.4 Hz), 7.18-7.41 (5H,m), 7.77 (2H, s), 7.80 (1H, s).

[0229] m/z (ES⁺) 434 (H+1, 4%), 176 (M-273, 100%).

[0230] Slower eluting isomer (b) (2SR, 3SR, 4SR, 2[(1′)SR]) (35 mg,yield 20%).

[0231]¹H-NMR (360 MHz, CDCl₃) δ1.48 (3H, d, J 6.6 Hz), 2.38-2.49 (1H,m), 2.84 (1H, dd, J 12.5 Hz, 7.9 Hz), 2.97 (1H, dd, J 12.4 Hz, 5.8 Hz),3.07 (1H, dd, J 7.5 Hz, 3.1 Hz), 3.90 (1H, t, J 8.7 Hz), 4.32 (1H, t, J8.0 Hz), 4.81 (1H, d, J 3.1 Hz), 4.90 (1H, q, J 6.6 Hz), 7.14-7.36 (5H,m), 7.63 (2H, s), 7.74 (1H, s).

[0232] m/z (ES⁺) 434 (H+1, 50%), 176 (M-273, 100%).

EXAMPLE 2

[0233] [(2SR, 3SR,4SR)-2-({(1SR)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]-N,N-dimethylmethanamine

[0234] [(25R, 3SR,4SR)-2-({(1SR)-1-[3,5-Bis(trifluoromethyl)phenyllethyl}oxy)-3-phenyltetrahydro-4furanyl]methanamine(Example 1(b); 52 mg), was dissolved in isopropanol (30 ml) and oneequivalent of etheral HCl was added. The reaction mixture was degassedwith nitrogen before the addition of formaldehyde (37% in water, 0.25ml) and 10% palladium on carbon (15 mg). The reaction was shaken under50 psi of hydrogen for 3 hours. The solvent was removed in vacuo and theresidue was dispersed between ethyl acetate and saturated potassiumcarbonate solution. The aqueous layer was extracted with ethyl acetate(2×25 ml), the combined organic extracts were washed with brine, driedover MgSO₄, filtered and solvent removed in vacuo. Purification wascarried out by preparative TLC eluting with 5% methanol in ethyl acetatewith 0.2% ammonia to give the title compound (17 mg, yield 31%).

[0235]¹H-NMR (360 MHz, CDCl₃) δ1.48 (3H, d, J 6.6 Hz), 2.19 (6H, s),2.42-2.58 (3H, m), 3.05 (1H, dd, J 6.4 Hz, 2.8 Hz), 3.90 (1H, t, J 8.1Hz), 4.33 (1H, dd, J 8.7 Hz, 6.6 Hz), 4.80 (1H, d, J 2.9 Hz), 4.90 (1H,q, J 6.6 Hz), 7.12-7.31 (5H, m), 7.64 (2H, s), 7.69 (1H, s). m/z (ES⁺)462 (H+1, 100%).

EXAMPLE 3

[0236] (2SR, 3SR, 4SR, 2[(1′)]RS)2-(4-Aminomethyl-3-phenyl-tetrahydro-furan-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol

[0237] (2SR, 3SR, 4SR, 2[(1′)]SR)2-(3,5-Bis(trifluoromethyl)phenyl)-2-(4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol(Description 9(a); 53 mg, 0.084 mmol) was dissolved in methanol (5 ml)and paladium on carbon (10 mg) and ammonium formate (37.1 mg) were addedand the mixture refluxed for 1 hour. Further ammonium formate (20 mg)was added and the mixture refluxed for another hour. The catalyst wasfiltered off, the solvent was removed in vacuo and the residue purifiedusing preparative TLC plates in 6% methanol in dichloromethane and 0.2%ammonia. The product was removed from the silica by washing withmethanol (2×20 ml) and the solvent removed in vacuo. The residue wasdissolved in dichloromethane (10 ml) and dried over MgSO₄ to give thetitle compound (20.2 mg, 54%).

[0238]¹H-NMR (360 MHz, CDCl₃) δ2.52-2.54 (1H, m), 2.8-3.05 (2H, m), 3.17(1H, d, J 4.4 Hz), 3.69 (2H, d, J 5.0 Hz), 4.07 (1H, t, J 8.6 Hz), 4.35(1H, t, J 8.3 Hz), 4.89 (1H, t, J 5.7 Hz), 4.97 (1H, d, J 2.5 Hz),7.16-7.35 (5H, m), 7.70 (2H, s), 7.74 (1H, s). m/z (ES⁺) 450 (M+H, 3%),176 (M-273, 100%).

EXAMPLE 4

[0239] (2SR, 3SR, 4SR, 2[(1′)]SR):2-(4-Aminomethyl-3-phenyl-tetrahydrofaran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol

[0240] (2SR, 3SR, 4SR, 2[(1′)]RS)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol

[0241] (Description 9(b); 33 mg) was hydrogenated using proceduredescribed in Example 3. Purification was carried out on preparative TLCeluting with 6% methanol in dicbloromethane containing 0.2% ammonia togive the title compound (9.2 mg yield 41%).

[0242]¹H-NMR (360 MHz, CDCl₃) δ2.38 (1H, m), 2.82 (1H, dd, J 12.5 Hz,7.3 Hz), 2.97 (1H, dd, J 12.5 Hz, 7.3 Hz), 3.25(1H, dd, J 6.9 Hz, 2.4Hz), 3.58 (1H, t, J 8.7 Hz), 3.64-3.70 (2H, m), 4.13 (1H, t, J 8.3 Hz),5.3 (1H, t, J 5.5 Hz), 5.26 (1H, d, J2.5 Hz), 7.18-7.38 (5H, m), 7.2(3H, s). m/z (ES⁺) 450 (M+H,3%), 176 (M-273, 100%).

EXAMPLE 5

[0243] (2RS)-2-[3,5-Bis(triluoromethyl)phenyl]-2-({(2SR, 3SR,4SR)-4-(N,N-dimethylamino)methyl]-3-phenyltetrahydro-2-faranyl}oxy)ethanol

[0244] (2SR, 3SR, 4SR, 2[(1′)]SR) 2-(4-omethyl-3-phenyl-tetrahydrofuran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol((Example 4; 76 mg) was reductively aminated using the proceduredescribed in Example 2. Purification was carried out by flash silicachromatography eluting with increasing concentrations of methanol (1-4%)in dichloromethane with 0.2% ammonia to give the title compound (50 mg,yield 62%).

[0245]¹H-NMR (400 MHz, CDCl₃) δ2.18 (6H, s), 2.41 (1H, dd, J 11.9 Hz,5.3 Hz), 2.51 (1H, t, J 9.4 Hz), 2.55-2.67 (1H, m), 3.13 (1H, dd, J 7.7Hz, 4.4 Hz), 3.65-3.74 (2H, m), 3.97 (1H, t, J 8.8 Hz), 4.37 (1H, dd, J8.6 Hz, 7.3 Hz), 4.82 (1H, dd, J 7.1 Hz, 3.6 Hz), 5.01 (1H, d, J 3.3Hz), 7.13-7.32 (5H, m), 7.69 (2H, s), 7.74 (1H, s). m/z (ES⁺) 478 (M+1,15%), 204 (M-273, 100%).

[0246] (a) [(2RS, 3RS,4SR)-2-({(1SR)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine;and

[0247] (b) [(2RS, 3RS,4SR)-2-({(1RS)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]methanamine

[0248] (2RS, 3SR, 4SR)N,N-Dibenzyl-{5-[1-(3,5-bis(trifluoromethyl)phenyl)-vinyloxy]-4phenyl-tetrahydrofaran-3-ylmethyl}amine(Description 10; 166 mg) was hydrogenated using the procedure describedin Example 1. Purification was carried out by flash chromatographyelution in increasing concentrations (0-5%) methanol in ethyl acetatewith 0.2% ammonia. Faster eluting isomer (a) (2RS, 3RS, 4SR, 2[(1′)]SR)(12 mg, yield 10%).

[0249]¹H-NMR (360 MHz, CDCl₃) δ1.21 (3H, d, J 6.5 Hz), 2.67 (1H, dd, J14.1 Hz), 2.84-2.96 (2H, m), 3.05 (1H, dd, J 10.7 Hz, 4.4 Hz), 3.69 (1H,t, J 8.2 Hz), 4.10 (1H, t, J 8.2 Hz), 4.72 (1H, q, J 6.4 Hz), 5.24 (1H,d, J 4.5 Hz), 7.24 (5H, m), 7.72 (2E, s), 7.75 (1H, s). m/z (ES⁺) 434(H+1, 20%), 176 (M-273, 100%).

[0250] Slower eluting isomer (b) (2RS, 3RS, 4SR, 2[(1′)]RS) (30 mg,yield 25%).

[0251]¹H-NMR (360 MHz, CDCl₃) δ1.40 (3H, d, J 6.6 Hz), 2.70 (1H, dd, J12.4 Hz), 2.86-3.06 (3H, m), 3.82 (1H, t, J 7.4 Hz), 4.40 (1H, t, J 7.4Hz), 4.82- 4.92 (2H, m), 7.22-7.36 (7H, m), 7.64 (1H, s). m/z (ES⁺) 434(H+1, 30%), 176 (M-273, 100%).

EXAMPLE 7

[0252] [(2RS, 3RS,4SR)-5-({(1RS)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethyl}oxy)-3-phenyltetrahydro-4-furanyl]-N,N-diethylmethanamine

[0253] [(2RS, 3RS,4SR)-2-({(1RS)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3-phenyltetrahydro-4-furanyllmethanamine(Example 6b; 30 mg) was methylated using the same procedure as describedin Example 2. Purification was carried out by preparative TLC elutingwith 3.5% methanol in ethyl acetate with 0.2% ammonia to give the titlecompound (3.6 mg).

[0254]¹H-NMR (360 MHz, CDCl₃) δ1.39 (3H, d, J 6.6 Hz), 2.25 (6H, s),2.35-2.40 (2H, m), 2.88 (1H, dd, J 11.2 Hz, 4.6 Hz), 3.06-3.08 (1H, m),3.85 (1H, t, J 8.3 Hz), 4.43 (1H, t, J 8.3 Hz), 4.84 (1H, q, J 7.6 Hz),7.24-7.38 (7H,m), 7.64 (1H, s). m/z (ES⁺) 462 (H+1, 100%).

EXAMPLE 8

[0255] (2RS, 3SR, 4SR, 2[(1′)]RS)2-(4-Aminomethyl-3-phenyl-tetrahydrofuran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol

[0256] (2RS, 3SR, 4SR, 2[(1′)]RS)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol(Description 11a; 23 mg) was hydrogenated as described in Example 3.Purification was carried out on preparative TLC eluting with 6% methanolin dichloromethane containing 0.2% ammonia (10.6 mg yield 65%).

[0257]¹H-NMR (360 MHz, CDCl₃) δ2.70 (1H,dd, J 13.3 Hz, 7.2 Hz), 2.92(1H, dd, J 13.3 Hz, 5.5 Hz), 2.99-3.06 (1H, m), 3.15 (1H, dd, J 11.7 Hz,5.5 Hz), 3.40 (1H, dd, J 12.1 Hz, 4.7 Hz), 3.48 (1H, dd, J 12.1 Hz, 4.7Hz), 3.69 (1H, t, J 8.2 Hz), 4.09 (1H, t, J 8.2 Hz), 4.58 (1H, dd, J 8.2Hz, 4.7 Hz), 5.24 (1H, d, J 5.5 Hz), 7.30-7.45 (5H, m), 7.74 (2H, s),7.79 (1H, s). m/z (ES⁺) 450 (M+H, 3%) 176 (M-273, 100%).

EXAMPLE 9

[0258] (2RS, 3SR, 4SR, 2[(1′)]SR)2-(4-Amiinomethyl-3-phenyl-tetrahydrofuran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol

[0259] (2RS, 3SR, 4SR, 2[(1′)]SR)2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol(Description 11b; 33 mg) was hydrogenated as described in Example 3.Purification was carried out on preparative TLC eluting with 5% methanolin dichloromethane containing 0.2% ammonia (14.9mg yield 65%).

[0260]¹H-NMR (360 MHz, CDCl₃) δ2.66-2.79 (1H, m), 2.95-3.17 (3H, m),3.58 (1H, dd, J 11.8 Hz, 7.5 Hz), 3.68 (1H, dd, J 11.8 Hz, 3.2 Hz), 3.88(1H, t, J 8.0 Hz), 4.47 (1H, t, J 8.0 Hz), 4.77 (1H, dd, J 7.4 Hz, 3.1Hz), 5.04 (1H, d, J 4.2 Hz), 7.21-7.37 (7H, m), 7.68 (1H, s). m/z (ES⁺)450 (M+H, 3%) 176 (M-273, 100%).

1. A compound of the formula (I):

wherein R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl; R² ishydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxy substitutedby C₁₋₄alkoxy; R³ is hydrogen, halogen or fluoroC₁₋₆alkyl; R⁴ ishydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined; R⁵ ishydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxy substitutedby C₁₋₄alkoxy; R⁶ represents hydrogen or a C₁₋₄alkyl group optionallysubstituted by a hydroxy group; R⁷ represents halogen, hydroxy,C₂₋₄alkenyl, C₂₋₄alkynyl, N₃, —NR¹⁰R¹¹, NR^(a)COR^(b), —OSO₂R^(a),—(CH₂)_(p)NR^(a)(CH₂)_(q)COOR^(b), COR^(a), COOR^(a), —N═C═O, or a fivemembered or six membered nitrogen-containing heteroaromatic ringoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O and S which heteroaromatic ring is optionally substituted at anysubstitutable position by a substituent selected from ═O, ═S, halogen,hydroxy, —SH, COR^(a), CO₂R^(a), -ZNR¹⁰R¹¹, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,fluoroC₁₋₄alkyl, chloroC₁₋₄alkyl, C₁₋₄alkoxy, fluoroC₁₋₄alkoxy orC₁₋₄alkoxy substituted by a C₁₋₄alkoxy or hydroxyl group, and whereinsaid C₂₋₄alkenyl and C₂₋₄alkynyl groups are optionally substituted by asubstituent selected from halogen, hydroxy, N₃, —NR¹⁰R¹¹,—NR^(a)COR^(b), —OSO₂R^(a), —(CH₂)_(p)NR^(a)(CH₂)_(q)COOR^(b), COR^(a)or COOR^(a); or R⁷ represents a C-linked nitrogen-containing ring of theformula

wherein A represents NR¹⁴ or O, and B represents a bond, CH₂, NR¹⁴ or O,wherein one or both hydrogen atoms in said CH₂ moiety may be replacedwith one or both of R¹² and R¹³, or alternatively, one of the hydrogenatoms in said CH₂ moiety together with a hydrogen atom from an adjacentcarbon are replaced by a double bond; with the proviso that when A is O,then B is NR¹⁴; and with the further proviso that when R⁷ representssaid C-linked nitrogen-containing ring, n is zero and R⁸ is hydrogen; R⁸represents hydrogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl, hydroxy, C₁₋₆alkoxy orhydroxyC₁₋₆alkyl; R⁹ represents hydrogen, halogen, C₁₋₆alkyl, CH₂OR^(c),oxo, CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b) are as previouslydefined and R^(c) represents hydrogen, C₁₋₆alkyl or phenyl; R¹⁰ ishydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloallylC₁₋₄alkyl, C₂₋₄alkylsubstituted by a C₁₋₄alkoxy or hydroxyl group, or R¹⁰ is a five memberedor six membered nitrogen-containing heteroaromatic ring as previouslydefined; R¹¹ is hydrogen or C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloaIkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group; or R¹⁰, R¹¹ and the nitrogen atom to which they areattached form a heteroaliphatic ring of 4 to 7 ring atoms, optionallysubstituted by one or two groups selected from hydroxy, COR^(e),CO₂R^(e), C₁₋₄alkyl optionally substituted by a C₁₋₄alkoxy or hydroxylgroup, or C₁₋₄alkoxy optionally substituted by a C₁₋₄alkoxy or hydroxylgroup, or a five membered or six membered nitrogen-containingheteroaromatic ring as previously defined, or said heteroaliphatic ringis substituted by a spiro-fused lactone ring or a spiro-fused ring ofthe formula —(CH₂)_(r)O(CH₂)_(s)— (where r and s are each independentlyzero, 1, 2 or 3 and the sum total of r and s is 3), and saidheteroaliphatic ring optionally containing a double bond, whichheteroaliphatic ring may optionally contain an oxygen or sulphur ringatom, a group S(O) or S(O)₂ or a second nitrogen atom which will be partof a NH or NR^(d) moiety, where R^(d) is C₁₋₄alkyl optionallysubstituted by hydroxy or C₁₋₄alkoxy, and where R^(e) is hydrogen,C₁₋₄alkyl or benzyl; or R¹⁰, R¹¹ and the nitrogen atom to which they areattached form a non-aromatic azabicyclic ring system of 6 to 12 ringatoms; or R¹⁰, R¹¹ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzenering or a five membered or six membered nitrogen-containingheteroaromatic ring optionally containing 1, 2 or 3 additionalheteroatoms selected from N, O and S; R¹² and R¹³ each independentlyrepresent hydrogen, hydroxy, COR^(e), CO₂R^(e), C₁₋₄alkyl optionallysubstituted by a C₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxy optionallysubstituted by a C₁₋₄alkoxy or hydroxyl group; or, when they areattached to the same carbon atom, R¹² and R¹³ may together represent ═O,═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(k)—, —CH₂OCH₂C(O)—,—CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—, —C(CH₃)₂OCH₂CH₂—,—CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—, —C(O)OC(CH₃)₂CH₂—,—C(O)OCH₂C(CH₃)₂—, —OCH₂(CH2)_(k)—, —OC(CH₃)₂CH₂CH₂—, —OCH2C(OCH₃)₂CH₂—,—OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH2C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula

or, where they are attached to adjacent carbon atoms, R¹² and R¹³ maytogether represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹² and R¹³ maytogether form a fused benzene ring; or, R¹² and R¹³ together form aC₁₋₂alkylene bridge across the pyrrolidine, piperidine, morpholine orpiperazine ring to which they are attached; R¹⁴ represents hydrogen,benzyl, C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyl C₁₋₄alkyl, orC₂₋₄alkyl substituted by a C₁₋₄alkoxy or hydroxyl group; R¹⁵ representshydrogen, halogen, hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orfluoroC₁₋₄alkyl; Z represents a bond, C₁₋₆alkylene or C₃₋₆cycloalkylene;k is 1, 2 or 3; m is 1 or 2; n is zero, 1 or 2; p is 1 or 2; and q is 1or 2; or a pharmaceutically acceptable salt thereof.
 2. A compound asclaimed in claim 1 wherein R¹ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,halogen or CF₃.
 3. A compound as claimed in claim 1 or claim 2 whereinR² is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.
 4. A compound asclaimed in any one of claims 1 to 3 wherein R³ is hydrogen, fluorine,chlorine or CF₃.
 5. A compound as claimed in any one of claims 1 to 4wherein R⁴ is hydrogen or fluorine.
 6. A compound as claimed in any oneof claims 1 to 5 wherein R⁵ is hydrogen, fluorine, chlorine or CF₃.
 7. Acompound as claimed in any one of claims 1 to 6 wherein R⁶ is C₁₋₄alkyloptionally substituted by hydroxy.
 8. A compound as claimed in any oneof claims 1 to 7 wherein R⁷ is NR¹⁰R¹¹ where the group NR¹⁰R¹¹represents a heteroaliphatic ring of 4 to 7 ring atoms substituted bytwo groups, the first substituent being selected from hydroxy, CO₂R^(e)(where R^(e) is hydrogen, methyl, ethyl or benzyl), or C₁₋₂alkylsubstituted by hydroxy, and the second substituent being a methyl group.9. A compound as claimed in any one of claims 1 to 8 wherein R⁸ ishydrogen or methyl.
 10. A compound as claimed in any one of claims 1 to9 wherein n is 1 or
 2. 11. A compound as claimed in any one of claims 1to 10 wherein R⁹ is hydrogen.
 12. A compound as claimed in claim 1 ofthe formula (Ia):

wherein A¹ is fluorine or CF₃; A² is fluorine or CF₃; A³ is fluorine orhydrogen; A⁴ is fluorine or hydrogen; A⁵ is methyl or hydroxymethyl; andR⁷ and n are as defmed in claim 1; or a pharmaceutically acceptable saltthereof
 13. A compound as claimed in any preceding claim for use intherapy.
 14. A pharmaceutical composition comprising a compound asclaimed in any one of claims 1 to 12, together with at least onepharmaceutically acceptable carrier or excipient.
 15. A method for thetreatment or prevention of physiological disorders associated with anexcess of tachykinins, which method comprises administration to apatient in need thereof of a tachykinin reducing amount of a compoundaccording to claim
 1. 16. A method for the treatment or prevention ofpain or inflammation, migraine, emesis, postherpetic neuralgia,depression or anxiety, which method comprises administration to apatient in need thereof of a therapeutically effective amount of acompound according to claim
 1. 17. Use of a compound as claimed in anyone of claims 1 to 12 for the manufacture of a medicament for thetreatment or prevention of physiological disorders associated with anexcess of tachykinins.
 18. Use of a compound as claimed in any one ofclaims 1 to 12 for the manufacture of a medicament for the treatment orprevention of pain or inflammation, migraine, emesis, postherpeticneuralgia, depression or anxiety.